Process of preparing polymeric nanoparticles that chelate radioactive isotopes and have a surface modified with specific molecules targeting the psma receptor and their use

Abstract

Process for preparation of polymeric nanoparticles that chelate radioactive isotopes and have their surface modified with specific molecules targeting PSMA receptor on the surface of cancer cells, with a targeting agent modified by a linker molecule attaching to free aldehyde groups present in the dextran chain. Polymeric nanoparticles that chelate radioactive isotopes synthesized according to the claimed process for use in therapy and diagnostics of prostate cancer and metastatic cancer cells as well as other affected cells for which the nanoparticles show the affinity.

1 . A process for preparing polymeric nanoparticles that chelate radioactive isotopes and have their surface modified with specific molecules targeting the PSMA receptor on the surface of cancer cells, characterized in that it comprises the stages in which:
 a) a dextran chain is oxidized to polyaldehyde by means of periodate,   b) a targeting agent that is α,α-urea of glutamic acid and lysine, the targeting agent modified by a linker molecule is attached to free aldehyde groups present in the dextran chain,   c) a folding agent in the form of hydrophobic diamine or polyamine is attached, with one or two amino groups of the folding agent attaching to aldehyde groups,   d) the resulting imine bonds are reduced to amine bonds,   e) to the free amino group of the attached folding agent, a chelator molecule is attached via an amide bond,   f) the resulting mixture is purified,   g) the nanoparticle fraction is subjected to lyophilization.   
     
     
         2 . The process according to  claim 1 , wherein the mixture from stage f) is purified by dialysis. 
     
     
         3 . The process according to  claim 1 , wherein the cells on which the PSMA receptor is present are prostate cancer cells and metastatic prostate cancer cells. 
     
     
         4 . The process according to  claim 1 , wherein the cells on which the PSMA receptor is present are breast, lung, colon and pancreatic cancer cells. 
     
     
         5 . The process according to  claim 1 , wherein the substitution of the aldehyde groups with the targeting agent is from 1 to 50%. 
     
     
         6 . The process according to  claim 5 , wherein the substitution of the aldehyde groups with the targeting agent is from 2.5 to 5%. 
     
     
         7 . The process according to  claim 1 , wherein the chelators are derivatives of DOTA, DTPA and/or NOTA. 
     
     
         8 . (canceled) 
     
     
         9 . The process according to  claim 1 , wherein the linker is 2,5-dioxopyrrolidin-1-yl 2,2-dimethyl-4-oxo-3,8,11,14,17,20-hexaoxa-5-azatricos-23-ate (PEG 5 ). 
     
     
         10 . The process according to  claim 1 , wherein the folding agent are lipophilic diamines selected from the group consisting of dodecylamines, diaminooctanes, diaminodecanes (DAD), polyether diamines, polypropylene diamines and block copolymer diamines. 
     
     
         11 . The process according to  claim 1 , wherein the obtained nanoparticles are radiochemically labelled with such isotopes in which the breakdown pathway involves beta plus decay, beta minus decay, gamma emitter decay. 
     
     
         12 . Polymeric nanoparticles chelating radioactive isotopes, with a surface modified by specific molecules targeting the PSMA receptor as obtained according to the process of  claim 1 , for use in diagnostics and therapy. 
     
     
         13 . Polymeric nanoparticles chelating radioactive isotopes according to  claim 12  for use in Positron Emission Tomography PET and PET/MRI diagnostics. 
     
     
         14 . Polymeric nanoparticles chelating radioactive isotopes according to  claim 12  for use in focal brachytherapy. 
     
     
         15 . Polymeric nanoparticles chelating radioactive isotopes prepared according to the process of  claim 1  for use in the therapy and diagnostics of prostate cancer and metastatic cancer as well as other cancers with affected cells to which the nanoparticles show the affinity.